Related Articles

Article Simons e.a.: Observed versus modelled lifetime overall survival of targeted therapies and immunotherapies for advanced non-small cell lung cancer patients – A systematic review. Critical Reviews in Oncology/Hematology, 153, p.103035. https://doi.org/10.1016/j.critrevonc.2020.103035

Article Frederix e.a.: Micro-costing Diagnostics in Oncology: From Single-Gene Testing to WholeGenome Sequencing. http://dx.doi.org/10.1101/19009969

Article Giesbertz e.a. : a duty to recontact in genetics: context matters https://www.nature.com/articles/s41576-019-0121-7

Article Mitchell e.a.: Experts reflecting on the duty to recontact patients and research participants; why professionals should take the lead in developing guideline. https://www.sciencedirect.com/science/article/pii/S1769721219300035?via%3Dihub (Corrected proofs)

Article Ploem e.a.: A duty to recontact in the context of genetics: futuristic or realistic? https://research.utwente.nl/en/publications/a-duty-to-recontact-in-the-context-of-genetics-futuristic-or-real

Article van de Ven e.a.: Variation in the time to treatment for stage III and IV Non-Small Cell Lung Cancer patients for hospitals in the Netherlands https://doi.org/10.1016/j.lungcan.2019.05.023

Article PATH Eijkelenboom e.a. : Recommendations for clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics https://link.springer.com/article/10.1007%2Fs00428-019-02555-3

Personalized medicine driven treatments in major diseases like advanced melanoma and non-small cell lung cancer (NSCLC) offer important health benefits to genetic subgroups, but can be expensive and may induce severe side effects. Whole Genome Sequencing (WGS) simultaneously tests for all relevant genetic aberrations in tumor tissue from individual cancer patients thereby allowing immediate selection of optimal therapy. This approach is likely to improve patient survival, avoid adverse effects, and to assist in controlling health care costs by offering treatment to only those identified to benefit.

The project team consists of a large nation-wide consortium embedded in the Center for Personalized Cancer Treatment (CPCT)/Hartwig Medical Foundation (HMF), covering all relevant disciplines (geneticists, pathologists, bio-informatics, cancer biologists, oncologists, health economists and ethical/legal experts). This approach will provide evidence for decision making on genetic testing for optimizing health and economic outcomes for current and future personalized cancer care.

Click 'read more' below for extensive information about the project.

Project abstract

Advanced Non-Small Cell Lung Cancer (NSCLC) (incidence ~9,000 in NL) and melanoma (incidence ~1,000) are both major diseases with a substantial burden for patients, caregivers, health care and society. Both are very heterogeneous with high mutation frequency in the tumors. For both NSCLC and malignant melanoma, targeted drugs for a number of specific driver mutations have become available for treatment in specific subgroups and are being evaluated as monotherapy or, to overcome tumor resistance, in combination with other targeted therapies. However, genetic make-up changes during course of disease, leading to tumor resistance. Genetic testing of NSCLC and malignant melanoma is required to guide these targeted treatments and is rapidly evolving in pathology laboratories. The recent breakthrough of Immunotherapeutics has even larger impact on the treatment of both diseases, but only for a minority of patients. No biomarker has yet been developed to accurately identify patients who will or will not respond to immunotherapy, and detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response . Accurate genetic tumor profiling of these cancers is thus essential to fully realize the value that both immune and targeted therapy can offer, but also to avoid potential harm.

Because of the complex genetic make-up of tumors and their evading mechanisms and the steadily increasing numbers of genetic biomarkers, testing with single- or (small) Targeted Gene Panels (TGPs) might not always be optimal or up-to-date and well-informed decision-making. Currently in the Netherlands, genetic testing is not regulated at a national level; different approaches (single target tests, a diverse range of TGPs, and in clinical research projects and trials Whole Exome and Whole Genome sequencing) are fragmented across centers and diseases. This could lead to different treatment strategies and outcomes in each hospital. Secondly, TGPs have very limited utility for the identification of novel biomarkers that are urgently needed to further improve decision-making and optimizing cancer care.

Technology developments in the field of Next Generation Sequencing now make it possible to apply WGS to capture a near-complete view of the various types of somatic mutations present in the tumor. While costs for WGS have come down spectacularly over the past years, the per patient test costs are obviously higher compared to TGPs.

The main open question that we will address in this project is whether the added information (direct for patient diagnostics and indirect by systematic databasing facilitating novel biomarker discovery) obtained by WGS does justify the extra costs and under which conditions. The most important questions in this respect are: Do we obtain relevant information for defining new biomarkers; what information is required to influence treatment decisions; how large should the decision-making effects be to make WGS cost-effective by reducing overtreatment; what are the most optimal models for applying WGS and TGPs, should we apply WGS for all novel (expensive) drugs and TGPs for the resulting optimized routine phase? Determining the potential added value of currently non-informative data for improving care for future patients is an intrinsic and key part of our goal using health economic decision models. Decision modeling is ideal setting and allows to use various sources in a consistent way.

We propose to assess the cost-effectiveness of NGS-based techniques by considering organizational and implementation issues in the Netherlands and putative stratified treatment benefits by comparing WGS with currently used routine molecular profiling approaches for patients with advanced melanoma or NSCLC that are treated with targeted therapies and with immune therapy. By monitoring treatment outcome, we will be able to assess the efficacy of existing and novel biomarkers. Furthermore, we will model long-term cost-effectiveness, budget impact, and relevant organizational issues related to the responsible introduction of WGS compared to current diagnostics.

Objectives of the current proposal are therefore:

A) to expand molecular profiling of tumors to improve immune- and targeted treatment selection in patients with advanced melanoma or NSCLC, and

B) to determine the cost-effectiveness and budget impact of WGS to facilitate responsible introduction.

The project consists of 6 Work Packages:

1)Diagnostic value of WGS,

2)Treatment decisions based on WGS,

3)Prediction of long-term health benefits and harms by micro-simulation,

4)Tumor-overarching early cost-effectiveness modelling,

5)Nation-wide organization of WGS,

6)Ethical, Legal and Societal Implications (ELSI) of WGS.

Collaborating centres

Nederlands Kanker Instituut-Antoni van Leeuwenhoek (NKI-AVL)
Universitair Medisch Centrum Utrecht (UMCU)
Maastricht Universitair Medisch Centrum (MUMC+)
Erasmus Medisch Centrum (EMC)
Universitair Medisch Centrum Groningen (UMCG)
Amsterdam UMC (locatie VUmc)
Universiteit Twente (UT)
Center for Personalized Cancer Treatment (CPCT), platform for clinical data of WGS patients
Hartwig Medical Foundation (HMF), WGS facility

The work packages in detail

WP1 - Costs

The costing part of WP1 is divided in three different objectives. 1) Microcosting of Whole Genome Sequencing, 2) Early HTA, budget impact of implementing WGS and 3) overview and costs of current diagnostics in clinical care pathways for melanoma and lung cancer. All analyses will give us upfront insights into the costs of WGS (1), the potential and future value of WGS for every tumor type and treatment (2) and the diagnostics which could be obsolete in this diagnostic process in the future. (3) Costing outcomes of this WP will be used as input to all other WPs.

WP1 - Diagnostic value of WGS

WP1 focuses on the comparison between WGS and current molecular diagnostics performed in different centers nationwide. The three different aims are outlined, that is (1) to address the logistical and data challenges related to implementation of WGS in the routine clinical landscape, (2) to identify the potential added therapeutic value of WGS and (3) to compare the total costs of WGS compared to current diagnostics.

WP2 - Treatment decisions based on WGS

The aim of WP2 is to prospectively demonstrate the value of whole genome sequencing (WGS) in patients diagnosed with advanced non-small cell lung cancer (NSCLC) and treated with immune checkpoint inhibitors. The aims are (1) to assess the added value of the application of WGS versus current diagnostics in terms of clinical outcomes and (2) to identify novel biomarkers that can predict response to immune therapy.

WP3 - Prediction of long-term health benefits and harms by micro-simulation

Overall objective of the work package: To assess long-term health outcomes and cost-effectiveness of using WGS-result (tumour load) as well as imaging data in the decision to provide immunotherapy in advanced non-small cell lung cancer (NSCLC) and melanoma patients, compared to current practice of immunotherapy treatment. Additional task: To assess progression-free survival and overall survival under different treatment regimes in current care for metastatic lung cancer & melanoma. Parametric survival models will be developed, and the association between survival/PFS and clinicopathological features will be assessed. This task is input for sub-question 5 and for WP4 in TANGO.

WP4 - Tumor-overarching early cost-effectiveness modelling

The aim of WP4 is to provide information on the cost-effectiveness, budget impact and wider public benefits of whole genome sequencing (WGS) versus current diagnostics-based care for advanced non-small cell lung cancer (NSCLC) and melanoma patients.

WP5 - Nation-wide organization of WGS

The aim of WP5 is to provide insights into the (requirements for) optimal implementation of whole genome sequencing (WGS) from a system level perspective. More specifically, what difficulties in the process of the implementation of WGS need to be overcome to achieve the optimal cost-effective implementation in the Netherlands? This research question can be divided into several separate steps. First, creating a detailed overview of the melanoma and non-small cell lung cancer (NSCLC) patient care pathways that are indicated for WGS, by means of literature search and stakeholder interviews. Second, deciding what the best modeling approach is to reflect the aforementioned implementation difficulties concerning the nation-wide implementation of WGS for personalized oncology. Third, modeling the system, and populating the model with the data from other work packages, interviews, registries, etc. In addition, the model will be verified and validated by discussing it with stakeholders. Fourth, drafting and simulating scenarios that subject the system to realistic changes that can affect the cost-effectiveness of WGS in the Netherlands.

WP5 - Ethics

To determine whether patients should be re-contacted about new genetic information that is discovered during research, and if so how this should be made operational in an ethically sound way, and to provide guidance for health care professionals and researchers on this topic.

WP6 - Ethical, Legal and Societal Implications (ELSI) of WGS

Is there a legal duty to recontact patients/participants, or the relatives of those who have undergone genome sequencing as part of clinical testing, therapeutic clinical research or observational research, if new information arises that is relevant to their diagnosis or treatment?

Article Giesbertz e.a. : a duty to recontact in genetics: context matters
- https://www.nature.com/articles/s41576-019-0121-7
Article Mitchell e.a.: Experts reflecting on the duty to recontact patients and research participants; why professionals should take the lead in developing guideline.
- https://www.sciencedirect.com/science/article/pii/S1769721219300035?via%3Dihub (Corrected proofs)
Article Ploem e.a.: A duty to recontact in the context of genetics: futuristic or realistic?
- https://research.utwente.nl/en/publications/a-duty-to-recontact-in-the-context-of-genetics-futuristic-or-real

Article van de Ven e.a.: Variation in the time to treatment for stage III and IV Non-Small Cell Lung Cancer patients for hospitals in the Netherlands
- https://doi.org/10.1016/j.lungcan.2019.05.023
Article PATH Eijkelenboom e.a. : Recommonadations for clinical intterpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics
- https://link.springer.com/article/10.1007%2Fs00428-019-02555-3

Disclaimer

The "Technology Assessment of Next Generation Sequencing in Personalized Oncology" (TANGO) project is funded by the ZonMw Personalised Medicine Programme under Dossier number: 846001002 in collaboration with KWF and Zilveren Kruis. The project period is 31 December 2016 – 31 May 2021.

This project works together with the PATH project and the CPCT-02 study.

Contact Details

Valesca Retèl, Ph.D. and Inge Eekhout at Netherlands Cancer Institute (NKI) Amsterdam.